The purpose of this R21 is to develop a non-human primate (NHP) model of TMS brain stimulation. The long- range utility of a NHP model of TMS is to accelerate the pace of development of human treatments. At present, human treatment trials lack a strong theoretical or empirical basis for selecting optimal ranges for a myriad of treatment parameters, including stimulus location, stimulus intensity, stimulus rate and stimulus pulse pattern, session duration, session spacing and session number. While these treatment parameters could all be exhaustively explored in humans, this would be inordinately costly and time consuming. A NHP model, once developed, will allow a wide range of treatment parameters to be explored systematically in a rapid, cost- effective manner. We envision systematic exploration of treatment parameters as the theme of an RO1 to be submitted after the NHP model has been successfully implemented and validated through the proposed aims. As promising ranges of TMS treatment parameters are determined, this information will be translated from the NHP model for human treatment trials. The primary focus of this proposal is to characterize the magnitude and spatial distribution properties of TMS-driven cerebral responses in an anesthetized baboon model, thereby validating and calibrating this new model relative to our prior and ongoing human work. To achieve this, we will systematically vary the orientation and intensity of the TMS-induced E-field, while measuring the TMS-induced responses with PET and EMG as biomarkers. These two stimulation parameters (orientation and intensity) were chosen because our prior human electrophysiological and imaging studies have provided strong evidence that they jointly determine the spatial distribution and magnitude of the TMS-induced response. From these prior studies, the PI and colleagues have developed mathematical models which formalize the postulated relationships, making explicit predictions of response magnitude at each brain location for any given coil geometry, location, orientation, and current. Use of the same modeling constructs in NHP and humans will facilitate inter-species translation. This proposal has two Specific Aims. Aim 1 is to confirm the orientation response predictions of the C3 model (Fox et al., 2004) in the NHP. Aim 2 is to confirm the intensity response predictions of the PRP model (Capaday et al., 1997;Fox et al., 2006) in the NHP. PUBLIC HEALTH RELEVANCE: Transcranial magnetic stimulation (TMS) has well-established applications in basic neuroscience and promising applications in neurological and psychiatric disorders. To fully capitalize on the potential utility of TMS, a better understanding of the effects of basic TMS parameters on neurophysiology is needed. The long- range goal of the research program motivating this proposal is to develop a knowledge base capable of guiding the rational development of transcranial magnetic stimulation (TMS) as: 1) a potential treatment for neurological and psychiatric disorders;and, 2) a tool for mapping inter-regional connectivity and for quantifying changes in synaptic efficacy induced by learning and rehabilitation.